tbuckley/cabot-search huggingface dataset:
Abstract LB509: ZG033, a novel CD137 agonist, induces superior anti-tumor activity without hepatotoxicity rely on Fc-mediated crosslinking
Authors: Liangwei Li, Wenting Liu, Guodong Shen, Dayan Zhang, Xiaoli Zheng, Liansheng Cheng
Journal: Cancer Research (2022)

Abstract CD137 (TNFRSF9, 4-1BB) is a member of the tumor necrosis factor receptor superfamily that functions as a co-stimulatory molecule of immunocytes. Agonistic antibodies against CD137 have shown promising therapeutic activity in mouse tumor models. However, molecules in the clinical development have shown limitations due to either dose-dependent severe liver toxicity (e.g. Urelumab), or modest antitumor activity (e.g. Utomilumab). We developed ZG033, a fully human IgG4 agonist of CD137 that engages with a exclusive epitope, to achieve a better efficacy and safety profile for immunotherapy. The biophysical properties and anti-tumor activities were determined using in vitro assays and in vivo mice xenograft models, respectively. ZG033 is a safe and potent antibody targeting a ligand competitive epitope, that conserved in human, cynomolgus monkey, and is associated with a differentiated pharmacology and toxicology profile. The complex structure of ZG033/CD137 was determined by X-ray crystallography. The binding affinity to human 4-1BB of ZG033 determined by Surface plasmon resonance (SPR) was moderate (KD=10 nM). ZG033 increased the production of IFN-γ by human CD8+T,CD4+T, NK cells in a Fcγ receptor-dependent manner, displaying an intermediate activation level between that of Urelumab and Utomilumab. In addition, it led to a dose-dependent increase in the CD137-driven NFκB reporter gene activation. In syngeneic mouse tumor models, ZG033 showed robust single agent anti-tumor activity starting from 0.3 mg/kg and induced durable antigen-specific immunological memory that prevents the growth of the same tumor cells in the mice re-challenged as compared to Utomilumab. Furthermore, ZG033 combined with an anti-PD-L1 antibody (Atezolizumab) significantly inhibited the growth of colorectal tumor in a human PBMC-engrafted humanized mouse model. Data from toxicology test in humanized CD137 transgenic mice showed that ZG033 was well-tolerated with normal ALT and AST levels. Even high dose of ZG033 (MTD≥180mg/kg) was achieved in cynomolgus monkeys with no abnormality in hematological indexes, important organs. These data demonstrate that ZG033 is a novel CD137 agonist that displays an favorable safety profile and has a potential in either mono- or combinational immunotherapies. Citation Format: Liangwei Li, Wenting Liu, Guodong Shen, Dayan Zhang, Xiaoli Zheng, Liansheng Cheng. ZG033, a novel CD137 agonist, induces superior anti-tumor activity without hepatotoxicity rely on Fc-mediated crosslinking [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB509.
Abstract 3299: Development of ONCR-788, a synthetic oncolytic virus based on Seneca Valley virus for the treatment of neuroendocrine tumors
Authors: Edward M. Kennedy, Agnieszka Denslow, Jacqueline Hewett, Lingxin Kong, Ana De Almeida, Jeffrey Bryant, Jennifer S. Lee, Judy Jacques, Sonia Feau, Hayes Hayes, Elizabeth L. McMichael, Daniel Wambua, Sanmit Adhikari, Jessica Deterling, Matthew Scott, Brian H. Haines, Mitchel H. Finer, Ted Ashburn, Christophe Quéva, Lorena Lerner
Journal: Cancer Research (2022)

Abstract Oncolytic viruses (OVs) are an emerging therapeutic approach for the treatment of cancer. Clinical benefit has been demonstrated for intratumoral administration. Still, the therapeutic effectiveness of intravenous delivery has been limited by neutralizing antibody responses against the virus. To circumvent this limitation, we developed Synthetic RNA viruses, a novel approach for intravenous and repeated administration of OVs, consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. Systemic administration of ONCR-788, the Synthetic RNA virus drug candidate encoding the vRNA of Seneca Valley virus (SVV), led to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. After a single intravenous administration of ONCR-788, we demonstrated vRNA delivery, viral replication, spread, and lysis of tumor cells. Robust anti-tumor efficacy was observed across diverse neuroendocrine tumor models, including tumor CDX and PDX xenografts, lung orthotopic, and GEMM-derived models. In a syngeneic model, ONCR-788 stimulated both tumor lysis and modulation of the tumor microenvironment. Enhanced T cell recruitment and activation, increased expression of PD-L1 on tumor cells and myeloid cells, and M2 to M1 macrophage conversion were observed. Combination of ONCR-788 with anti-PD-1 resulted in improved anti-tumor activity versus the monotherapy arms. Altogether, ONCR-788 provides an innovative approach that enables repeat intravenous administration of viral immunotherapy. Citation Format: Edward M. Kennedy, Agnieszka Denslow, Jacqueline Hewett, Lingxin Kong, Ana De Almeida, Jeffrey Bryant, Jennifer S. Lee, Judy Jacques, Sonia Feau, Hayes Hayes, Elizabeth L. McMichael, Daniel Wambua, Sanmit Adhikari, Jessica Deterling, Matthew Scott, Brian H. Haines, Mitchel H. Finer, Ted Ashburn, Christophe Quéva, Lorena Lerner. Development of ONCR-788, a synthetic oncolytic virus based on Seneca Valley virus for the treatment of neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3299.
Abstract 1677: Transcriptomic landscape of medulloblastoma reveals pathways of tumor-stroma remodelling
Authors: Ioanna Tsea, Yana Ruchiy, Manouk Verhoeven, Indranil Sinha, Klas Blomgren, Lena Maria Carlson, John Inge Johnsen, Cecilia Dyberg, Ninib Baryawno
Journal: Cancer Research (2022)

Abstract Medulloblastoma is one of the most common pediatric malignant brain tumors, currently comprising four distinct molecular subgroups: wingless [WNT], sonic hedgehog [SHH], and groups 3-4. Efforts to identify the mechanisms of medulloblastoma development have focused on mapping the extent of the tumor cell heterogeneity within each subgroup. Nevertheless, little is known about the role of the tumor microenvironment (TME) in medulloblastoma progression, particularly in subgroups 3-4, which have the worst prognosis due to metastatic disease. In this study, we performed single-cell transcriptomics on 14 human medulloblastoma samples spanning all molecular subgroups, to uncover novel TME-tumor interactions modulating medulloblastoma progression and metastasis. Unsupervised clustering of all medulloblastoma samples revealed 18 subclusters, including tumor granule neuron progenitors (GNPs) in different stages of differentiation, stromal cells (including oligodendrocyte precursors, mature oligodendrocytes, astrocytes, fibroblasts, endothelial cells and pericytes), myeloid cells (including microglia, monocytes and macrophages) as well as lymphoid cells. To investigate subgroup-specific signatures as well as TME-tumor pathways, we analyzed each subgroup separately. Analysis of supporting stroma cells in groups 3-4 demonstrated the presence of 8 different stroma populations, including a population of tumor-associated endothelial cells. Tumor-associated endothelial and fibroblast populations of groups 3-4 showed the highest expression of genes for vascular remodeling and extracellular matrix degradation, suggesting an active reprogramming of the stroma by tumor GNP cells to support medulloblastoma progression. Epithelial-to-mesenchymal transition-like processes that regulate stem cell, invasion and metastatic properties were upregulated in the tumor GNP populations of groups 3-4 compared to SHH and WNT subgroups. Finally, we highlight the presence of the CXCL1-CXCL5/CXCR2 metastasis-associated axis in groups 3-4 medulloblastomas as a potential therapeutic target. Our findings provide biological insights into TME processes for the different subgroups of medulloblastoma and possible new potential therapeutic avenues. Citation Format: Ioanna Tsea, Yana Ruchiy, Manouk Verhoeven, Indranil Sinha, Klas Blomgren, Lena Maria Carlson, John Inge Johnsen, Cecilia Dyberg, Ninib Baryawno. Transcriptomic landscape of medulloblastoma reveals pathways of tumor-stroma remodelling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1677.
Abstract 2637: Inhibition of novel kinase MAP3K19 reverses EMT and kills triple negative breast cancer cell lines
Authors: Khoa Nguyen, Thomas Cheng, Madlin Alzoubi, Steven Elliott, Sean Lee, David Drewry, Bridgette Collins-Burow, John Brognard, Matthew Burow
Journal: Cancer Research (2022)

Abstract The Triple-Negative Breast Cancer (TNBC) subtype is a breast cancer subpopulation whose phenotype lacks estrogen and progesterone growth receptors, and lacks HER2 amplification. This contrasts with the Luminal and HER2+ subpopulations for which clinical precision therapies exist to target cancer proliferation and improve prognoses. Consequently, the discovery of new targets is necessitated by the TNBC subtype, which has the poorest patient outcomes. Our studies have identified MAP3K19 as one such potential target. MAP3K19 an understudied protein kinase with poorly characterized physiological functions outside of its roles in the Mitogen-Activated Protein Kinase (MAPK) signaling cascade. Broadly, the MAPK signaling has been associated with cell proliferation and differentiation in pathways both intracellular and extracellular, which in the context of cancer cell biology warrants investigation into cancer cell behavior as well as the associated tumor microenvironment (TME). The Published Kinase Inhibitor Set (PKIS) is an open-access drug panel designed by GlaxoSmithKline to identify novel kinases. Preliminary PKIS cell-viability screening identified GSK1440913, GW494601, and GSK907232A as compounds with the most adverse effects on cell phenotype and growth in TNBC lines MDA-MB-231 and PDX-derived TU-BcX-49S. Analysis of common targets revealed MAP3K19 a common target, suggesting its importance in cancer cell growth and proliferation. AT-9283, a more specific MAP3K19 inhibitor, was used to support the initial results. Treatment with AT-9283 resulted in a dose-dependent killing effect. Furthermore, MAP3K19 inhibition resulted in decreased EMT gene signatures by qPCR. To summarize, MAP3K19 was identified by the PKIS screen as a major kinase in TNBC. Treatment with AT-9283, a more specific MAP3K19 inhibitor, resulted in cellular death and reversal in EMT gene signature by qPCR. Future directions for this project involve genetic knock-down and overexpression of MAP3K19 to evaluate its roles in biology and its signaling mechanisms. Citation Format: Khoa Nguyen, Thomas Cheng, Madlin Alzoubi, Steven Elliott, Sean Lee, David Drewry, Bridgette Collins-Burow, John Brognard, Matthew Burow. Inhibition of novel kinase MAP3K19 reverses EMT and kills triple negative breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2637.
Author Correction: Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies
Authors: Emily R. Kansler, Saïda Dadi, Chirag Krishna, Briana G. Nixon, Efstathios G. Stamatiades, Ming Liu, Fengshen Kuo, Jing Zhang, Xian Zhang, Kristelle Capistrano, Kyle A. Blum, Kate Weiss, Ross M. Kedl, Guangwei Cui, Koichi Ikuta, Timothy A. Chan, Christina S. Leslie, A. Ari Hakimi, Ming O. Li
Journal: Nature Immunology (2022)
Abstract 5468: A pharmacological inhibition of sterol O-acyltransferase 1improves response to enzalutamide in prostate cancer
Authors: Sora Q. Kim, Sagar Utturkar, Nadia M. Atallah, Kee-Hong Kim
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) growth is mediated by androgens via activation of androgen receptor (AR). Accordingly, androgen deprivation therapy (ADT) is the gold standard for the treatment of advanced PCa, but progression to castration-resistant PCa (CRPC) follows. Enzalutamide (ENZ) is an AR antagonist used for the management of CRPC. However, patients acquire resistance to the drug in a short period. Meanwhile, cholesterol is a precursor to androgen and its metabolism is dysregulated in PCa. In addition, cholesteryl ester (CE) accumulation aggravates tumor growth but its association with ENZ treatment has not been studied. Thus, we hypothesized that inhibition of CE formation by blockage of sterol-O-acyltransferase 1 (SOAT1) could enhance the response to ENZ. We found that SOAT1 mRNA is upregulated in clinical prostate tumors compared to normal/benign tissues in TCGA dataset. SOAT1 mRNA level was also highly correlated with AR expression in SU2CF/PCF cohorts and TCGA dataset, suggesting critical role of the cholesterol metabolism in prostate tumor progression and potential association to AR signaling pathway. We treated 22RV1 prostate cancer cells with ENZ in the presence or absence of SOAT1 inhibitor, avasimibe, and found the combination treatment effectively reduced the level of CEs compared to control, which accompanied inhibition of colony formation and cell proliferation. Combination index value was calculated and the relationship between the two drugs showed synergism. Furthermore, genetic knockdown of SOAT1 sensitized cells to ENZ treatment and also reduced the number of colonies formed. In TCGA dataset, patients who had previously undergone ADT were analyzed, and their Kaplan-Meier survival curve showed low SOAT1 expressing patients had a significantly longer progression-free survival rate than their counterpart, indicating that SOAT1 could act as a prognostic biomarker predicting PCa treatment outcome. Gene set enrichment analysis of patients with ADT history showed androgen response gen sets were enriched in high SOAT1 expressing PCa patient group. Inhibition of SOAT1 and the combination treatment did not change AR and ARV7 protein level, but downstream genes such as PSA were down regulated upon the combination treatment. In summary, our in vitro results showed blockage of SOAT1 enzyme sensitized PCa cells to ENZ treatment and analysis of PCa patient data suggested that SOAT1 gene expression has potential as a prognostic marker. Citation Format: Sora Q. Kim, Sagar Utturkar, Nadia M. Atallah, Kee-Hong Kim. A pharmacological inhibition of sterol O-acyltransferase 1improves response to enzalutamide in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5468.
Abstract 2567: Targeting TBL1/β-catenin complex using peptides designed to competitively inhibit aberrant Wnt signaling in cancer
Authors: Shelby Rheinschmidt, Trason Thode, Samuel Sampson, Alexis Weston, Tithi Ghosh Halder, Serina Ng, Ryan Rodriguez del Villar, Mohan Kaadige, Anton Zernov, Marcelle Machluf, Raffaella Soldi, Sunil Sharma
Journal: Cancer Research (2022)

Abstract Purpose: Canonical Wnt signaling is a key cascade in regulating development and stemness, however it can become dysregulated and tightly associated with oncogenesis. In human cancers, Wnt/β-catenin signaling is highly activated due to mutations of members associated with the pathway such as adenomatous polyposis coli (APC) and β-catenin. Transducin β-like protein 1 (TBL1) and highly related TBLR1, form a complex with β-catenin facilitating the translocation of β-catenin to the nucleus. The formation of this complex protects β-catenin from degradation by SIAH-1 ubiquitinase and aids β-catenin binding to TCF/LEF transcription factors to transcribe downstream Wnt target genes. We recently reported that the destruction of the TBL1/β-catenin complex using a small molecule results in ubiquitination of β-catenin and inhibition of downstream signaling. As an alternative approach, we designed a series of novel peptides to interfere with binding of β-catenin with TBL1. Methods: Homologous competitive ELISA and thermal shift assays were performed to identify potential peptides that were able to displace β-catenin from TBL1. Additionally, we evaluated the ability of the peptides to disrupt the TBL1/β-catenin complex by performing pull-down assays and monitored the levels of β-catenin ubiquitination in response to peptide treatment in colon cell lines. To assess the levels of TCF/LEF transcriptional activation downstream the Wnt/β-catenin pathway, we performed TOPFlash assays in Wnt-activated cells transfected with plasmids for peptide expression. Results: Our preliminary results identified a set of peptides that efficiently displaces β-catenin from TBL1. Homologous competitive ELISA showed that the peptides were able to displace β-catenin from TBL1 in a dose dependent manner. The top five peptide hits were then tested for their ability to inhibit Wnt signaling using the TOPFlash assay. Among these, one peptide in particular showed high efficiency in inhibiting TCF/LEF transcriptional activation downstream the Wnt/β-catenin pathway. Our study suggests that β-catenin therapeutic peptides may represent a new and exciting approach for Wnt driven cancer therapy. Citation Format: Shelby Rheinschmidt, Trason Thode, Samuel Sampson, Alexis Weston, Tithi Ghosh Halder, Serina Ng, Ryan Rodriguez del Villar, Mohan Kaadige, Anton Zernov, Marcelle Machluf, Raffaella Soldi, Sunil Sharma. Targeting TBL1/β-catenin complex using peptides designed to competitively inhibit aberrant Wnt signaling in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2567.
Abstract LB043: Identification and characterization of cancer-associated fibroblast subpopulations in lung adenocarcinoma
Authors: Daeseung Kim, Jeong Seon Kim, Seoree Kim, Sang Hoon Chun, Jae Jun Kim, Inyoung Cheon, Sieun Lee, Jung Sook Yoon, Soon Auck Hong, Hye Sung Won, Keunsoo Kang, Young-Ho Ahn, Yoon Ho Ko
Journal: Cancer Research (2022)

Abstract Background: Cancer-associated fibroblasts (CAFs) reside within the tumor microenvironment, facilitating cancer progression and metastasis via direct and indirect interactions with cancer cells as well as other stromal cell types. CAFs are comprised of heterogeneous subpopulations of activated fibroblasts, including myofibroblastic, inflammatory, or immunosuppressive CAFs. In this study, we sought to identify subpopulations of CAFs isolated from human lung adenocarcinomas and describe their transcriptomic as well as functional characteristics through single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatics analyses. Methods: We isolated and cultured two types of CAFs. Total CAFs were isolated after negative selection using cell-type-specific antibodies against lymphocytes (CD45), macrophages (CD68), endothelial cells (CD31), and epithelial cells (Ep-CAM). THY1+ CAFs were isolated after additional selection based on CAF-specific marker THY1. Total CAFs (n=5,139 cells) and THY1+ CAFs (n=4,038 cells) were subjected to 10X Genomics scRNA-seq. scRNA-seq data were then integrated and analyzed using the Seurat method. Results: Cell trajectory analysis of combined total and THY1+ CAFs revealed two branching points with five distinct branches. Based on Gene Ontology analysis, we denoted Branch 1 as “immunosuppressive”, Branch 2 as “neoantigen-presenting”, Branch 4 as “myofibroblastic”, and Branch 5 as “proliferative” CAFs. We selected representative branch-specific markers and measured their expression levels in total and THY1+ CAFs. We also investigated the effects of these markers on CAF activity under co-culture with lung cancer cells. Conclusions: This study describes novel subpopulations of CAFs in lung adenocarcinoma, highlighting their potential value as therapeutic targets. Citation Format: Daeseung Kim, Jeong Seon Kim, Seoree Kim, Sang Hoon Chun, Jae Jun Kim, Inyoung Cheon, Sieun Lee, Jung Sook Yoon, Soon Auck Hong, Hye Sung Won, Keunsoo Kang, Young-Ho Ahn, Yoon Ho Ko. Identification and characterization of cancer-associated fibroblast subpopulations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB043.
Abstract 384: Lipid nanoparticle aided delivery of a STING agonist to treat pancreatic cancer
Authors: Sherin George Shaji, Pratikkumar Patel, Kun Cheng
Journal: Cancer Research (2022)

Abstract The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a huge population of cancer-associated fibroblasts, myeloid-derived suppressor cells, regulatory T cells, and a scarce number of effector immune cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. Agonists of STING have been shown to inflame the TME, reduce tumor burden and confer anti-tumor activity in mouse models. 2’, 3’ cyclic guanosine monophosphate adenosine monophosphate (cGAMP) is a high-affinity endogenous ligand of STING. However, the cytosolic delivery of exogenous cGAMP to antigen-presenting cells and tumor cells remains a challenge due to poor cellular permeability, poor stability, and rapid clearance. We address these limitations by encapsulating cGAMP in a lipid nanoparticle (cGAMP-LNP) engineered for efficient cytosolic delivery. The size and morphology of the cGAMP-LNP were characterized using dynamic light scattering and TEM, respectively. The in-vitro activity of the cGAMP-LNP was determined in the THP-1 Blue࣪ ISG reporter cell line, whereas the endosomolytic activity of the LNP was evaluated by red blood cell hemolysis assay. The cGAMP-LNP activates the IRF3 pathway in-vitro and shows concentration- and pH-dependent endosomolytic activity. Moreover, the cGAMP-LNP was evaluated for cytotoxicity in-vitro and were found non-toxic to human pancreatic duct epithelial cell line at bioactive concentrations. Collectively, the cGAMP-LNP represents a promising strategy to convert immunosuppressive pancreatic cancer to immune-inflamed pancreatic cancer. Citation Format: Sherin George Shaji, Pratikkumar Patel, Kun Cheng. Lipid nanoparticle aided delivery of a STING agonist to treat pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 384.